PROJECT SUMMARY Although some human studies suggest that obesity impairs memory and cognition, this finding is not consistent and other groups have failed to find similar associations. Because the ?apple-shaped? anatomical pattern that accompanies visceral obesity has different physiological consequences than the 'pear-shaped' distribution that reflects subcutaneous adiposity, the variable cognitive outcomes reported in obese humans may be due to the use of weight/height ratios to define obesity. Visceral obesity is accompanied by peripheral inflammation and impairs memory, while subcutaneous adiposity does not activate the innate immune system and may protect against obesity-induced cognitive dysfunction. Resident microglia in the central nervous system represent the first line of defense against inflammation, and microglial activation in impairs synaptic plasticity and cognition in other disease models. Microglia regulate neuronal plasticity via receptor-mediated signaling and physical interactions involving synaptic phagocytosis or ?stripping,? but neither of these processes has been investigated in obesity. We hypothesize that visceral and subcutaneous adiposity exert opposing effects on synaptic stripping, and that microglial interactions with neurons determine the cognitive consequences of obesity.